Signal transduction proteins important in carcinogenesis and cancer progression present attractive targets for the development of novel anticancer therapeutics. The STAT (signal transducers and activators of transcription) family of proteins are DNA-binding proteins that play a dual role in signal transduction and activation of transcription. Six distinct members of the STAT family include STAT1, STAT2, STAT3, STAT4, STAT5, and STATE.
The activities of the STATs are modulated by various cytokines and mitogenic stimuli. Binding of a cytokine to its receptor results in the activation of Janus protein tyrosine kinases (JAKs) associated with these receptors. This phosphorylates STAT, resulting in translocation to the nucleus and transcriptional activation of STAT responsive genes. Phosphorylation on a specific tyrosine residue on the STATs results in their activation, resulting in the formation of homodimers and/or heterodimers of STAT which bind to specific gene promoter sequences. Events mediated by cytokines through STAT activation include cell proliferation and differentiation and prevention of apoptosis.
STAT3 is expressed in most cell types (Zhong et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 4806-4810), and induces the expression of genes involved in response to tissue injury and inflammation. STAT3 has been shown to prevent apoptosis through the expression of bc1-2 (Fukada et al., Immunity, 1996, 5, 449-460). STAT3 is a master regulator of genes controlling cell proliferation, survival, migration and immune suppression. Aberrant expression of or constitutive expression of STAT3 has been associated with a number of disease processes. Constitutive activation of STAT3 has been found in a wide variety of cancers and STAT3 has been found to be persistently activated in tumor cells as well as non-transformed cells in the tumor microenvironment.